Levofloxacin plus Metronidazole Administered Once Daily versus Moxifloxacin Monotherapy against a Mixed Infection of Escherichia coli and Bacteroides fragilis in an In Vitro Pharmacodynamic Model

Abstract

Moxifloxacin has been suggested as an option for monotherapy of intra-abdominal infections. Recent data support the use of a once-daily metronidazole regimen. The purpose of this study was to investigate the activity of levofloxacin (750 mg every 24 h [q24h]) plus metronidazole (1,500 mg q24h) compared with that of moxifloxacin (400 mg q24h) monotherapy in a mixed-infection model. By using an in vitro pharmacodynamic model in duplicate, Escherichia coli and Bacteroides fragilis were exposed to peak concentrations of 8.5 mg of levofloxacin/liter q24h, 32 mg of metronidazole/liter q24h, and 2 mg for moxifloxacin/liter q24h for 24 h. The activities of levofloxacin, metronidazole, moxifloxacin, and levofloxacin plus metronidazole were evaluated against E. coli, B. fragilis, and E. coli plus B. fragilis. The targeted half-lives of levofloxacin, metronidazole, and moxifloxacin were 8, 8, and 12 h, respectively. Time-kill curves were analyzed for time to 3-log killing, slope, and regrowth. Pre-and postexposure MICs were determined. The preexposure levofloxacin, metronidazole, and moxifloxacin MICs for E. coli and B. fragilis were 0.5 and 1, >64 and 0.5, and 1 and 0.25 mg/liter, respectively. Levofloxacin and moxifloxacin achieved a 3-log killing against E. coli and B. fragilis in all experiments, as did metronidazole against B. fragilis. Metronidazole did not decrease the starting inoculum of E. coli. The area under the concentration-time curve/MIC ratios for E. coli and B. fragilis were 171.7 and 85.9, respectively, for levofloxacin and 26 and 103.9, respectively, for moxifloxacin. Levofloxacin plus metronidazole exhibited the fastest rates of killing. The levofloxacin and moxifloxacin MICs for B. fragilis increased 8-to 16-fold after the organism was exposed to moxifloxacin. No other changes in the postexposure MICs were found. Levofloxacin plus metronidazole administered once daily exhibited activity similar to that of moxifloxacin against the mixed E. coli and B. fragilis infection. A once-daily regimen of levofloxacin plus metronidazole looks promising for the treatment of intra-abdominal infections.Intra-abdominal infections include peritonitis, appendicitis, and abscesses, among a wide variety of other infections. These infections are commonly caused by a mixture of aerobic and anaerobic bacteria, which creates an especially problematic situation. Not only do anaerobes act synergistically with facultative bacteria, but facultative organisms also facilitate the infectious process by promoting the growth of anaerobes (4).Escherichia coli and Bacteroides fragilis are the organisms most commonly isolated from intra-abdominal abscesses (12). B. fragilis is known to be the most important anaerobic pathogen but accounts for only 0.5% of the normal colonic flora (4). A capsular polysaccharide, adherence potential, piliation, and toxin production all contribute to the virulence of B. fragilis (4).The polymicrobial nature of intra-abdominal infections requires the use of either dual therapy or broad-spectrum monotherapy. ...

Kinetics and Quantification of Antibacterial Effects of Beta-Lactams, Macrolides, and Quinolones against Gram-Positive and Gram-Negative RTI Pathogens

“…Neither the MICs nor the MBCs, but the killing rate was the major determinant for in vivo efficacy. Likewise, in an in vitro pharmacodynamic model comparing the activities of moxifloxacin monotherapy with those of a combination/regimen of levofloxacin plus metronidazole in a mixed infection model of E. coli and Bacteroides fragilis, it became obvious that the MICs were not predictive for activity in the pharmacodynamic in vitro model [38]. This lack of correlation between pharmacodynamic activity and in vitro susceptibility testing results is also discussed elsewhere in this issue [39].…”

Fluoroquinolones and Anaerobes

“…Overall, the n p 1 combination of levofloxacin at 750 mg and metronidazole at 500 mg every 8 h or 1500 mg once daily appeared to have greater bactericidal activity than the regimen with metronidazole at 1000 mg once daily. The combination of 750 mg of levofloxacin plus metronidazole (1500 mg daily) was further investigated against monotherapy with moxifloxacin (400 mg daily) in an in vitro mixed infection model [84]. The combination of levofloxacin plus metronidazole produced very rapid 3-log killing against E. coli and B. fragilis.…”

Evaluación farmacocinética/farmacodinámica (PK/PD) de un esquema de administración oral de metronidazol en intervalo ampliado para el manejo de infecciones producidas por Bacteroides fragilis

“…Al respecto, Hermsen y cols. 23 , compararon la efectividad de un tratamiento asociado con levofloxacina y metronidazol en dosis diaria única versus un tratamiento simple con moxifloxacina. Para ellos, los autores determinaron la relación AUC/CIM de ambos tratamiento sobre cepas de Escherichia coli y B. fragilis en un modelo in vitro.…”